NAD(P)H-quinone oxidoreductase 1 induces complicated effects on mitochondrial dysfunction and ferroptosis in an expression level-dependent manner.

NAD(P)H-quinone oxidoreductase 1 (NQO1) is an essential redox enzyme responsible for redox balance and energy metabolism. Despite of its importance, the brain contains high capacity of polyunsaturated fatty acids and maintains low levels of NQO1 expression. In this study, we examined how levels of NQO1 expression affects cell survival in response to toxic insults causing mitochondrial dysfunction and ferroptosis, and whether NQO1 has a potential as a biomarker in different stressed conditions. Following treatment with rotenone, overexpressed NQO1 in SH-SY5Y cells improved cell survival by reducing mitochondrial reductive stress via increased NAD+ supply without mitochondrial biogenesis. However, NQO1 overexpression boosted lipid peroxidation following treatment with RSL3 and erastin. A lipid droplet staining assay showed increased lipid droplets in cells overexpressing NQO1. In contrast, NQO1 knockdown protected cells against ferroptosis by increasing GPX4, xCT, and the GSH/GSSG system. Also, NQO1 knockdown showed lower iron contents and lipid droplets than non-transfectants and cells overexpressing NQO1, even though it could not attenuate cell death when exposed to rotenone. In summary, our study suggests that different NQO1 levels may have advantages and disadvantages depending on the surrounding environments. Thus, regulating NQO1 expression could be a potential supplementary tool when treating neuronal diseases.

Effect of nicotinamide mononucleotide on osteogenesis in MC3T3-E1 cells against inflammation-induced by lipopolysaccharide.

Objective: Nicotinamide mononucleotide (NMN) is extensively utilized as an anti-aging agent and possesses anti-inflammatory properties. Lipopolysaccharide (LPS) activates Toll-like receptor 4, a process modulated by intracellular signaling pathways such as the Wnt/ß-catenin pathway. This study investigated the impact of NMN on osteogenesis in the presence of LPS. Methods: To elucidate the role of NMN in osteogenesis in the context of Gram-negative bacterial infection after LPS treatment, we cultured a mouse pre-osteoblast cell line (MC3T3-E1) and subsequently incubated it with NMN and/or LPS. We then evaluated osteogenic activity by measuring alkaline phosphatase activity, assessing gene expression and protein levels, and performing Alizarin Red S staining and immunocytochemistry. Results: MC3T3-E1 cells underwent successful differentiation into osteoblasts following treatment with osteogenic induction medium. LPS diminished features related to osteogenic differentiation, which were subsequently partially reversed by treatment with NMN. The restorative effects of NMN on LPS-exposed MC3T3-E1 cells were further substantiated by elucidating the role of Wnt/ß-catenin signaling, as confirmed through immunocytochemistry. Conclusion: This study showed that infection with Gram-negative bacteria disrupted the osteogenic differentiation of MC3T3-E1 cells. This adverse effect was partially reversed by administering a high-dose of NMN. Drawing on these results, we propose that NMN could serve as a viable therapeutic strategy to preserve bone homeostasis in elderly and immunocompromised patients.

Pioneering the future of cancer therapy: Deciphering the p53-ferroptosis nexus for precision medicine.

The TP53 gene, encoding the p53 protein, has been a focal point of research since its 1979 discovery, playing a crucial role in tumor suppression. Ferroptosis, a distinct form of cell death characterized by lipid peroxide accumulation, has gained prominence since its recognition in 2012. Recent studies have unveiled an intriguing connection between p53 and ferroptosis, with implications for cancer therapy. Recent research underscores p53 as a novel target for cancer therapy, influencing key metabolic processes in ferroptosis. Notably, p53 represses the expression of the cystine-glutamate antiporter SLC7A11, supporting p53-mediated tumor growth suppression. Furthermore, under metabolic stress, p53 mitigates ferroptosis sensitivity, aiding cancer cells in coping and delaying cell death. This dynamic interplay between p53 and ferroptosis has far-reaching implications for various diseases, particularly cancer. This review provides a comprehensive overview of ferroptosis in cancer cells, elucidating p53's role in regulating ferroptosis, and explores the potential of targeting p53 to induce ferroptosis for cancer therapy. Understanding this complex relationship between p53 and ferroptosis offers a promising avenue for developing innovative cancer treatments.

Enhancement of preimplantation mouse embryo development with optimized in vitro culture dish via stabilization of medium osmolarity.

OBJECTIVE: We evaluated the efficacy of the newly developed optimized in vitro culture (OIVC) dish for cultivating preimplantation mouse embryos. This dish minimizes the need for mineral oil and incorporates microwells, providing a stable culture environment and enabling independent monitoring of individual embryos. METHODS: Mouse pronuclear (PN) zygotes and two-cell-stage embryos were collected at 18 and 46 hours after human chorionic gonadotropin injection, respectively. These were cultured for 120 hours using potassium simplex optimized medium (KSOM) to reach the blastocyst stage. The embryos were randomly allocated into three groups, each cultured in one of three dishes: a 60-mm culture dish, a microdrop dish, and an OIVC dish that we developed. RESULTS: The OIVC dish effectively maintained the osmolarity of the KSOM culture medium over a 5-day period using only 2 mL of mineral oil. This contrasts with the significant osmolarity increase observed in the 60-mm culture dish. Additionally, the OIVC dish exhibited higher blastulation rates from two-cell embryos (100%) relative to the other dish types. Moreover, blastocysts derived from both PN zygotes and two-cell embryos in the OIVC dish group demonstrated significantly elevated mean cell numbers. CONCLUSION: Use of the OIVC dish markedly increased the number of cells in blastocysts derived from the in vitro culture of preimplantation mouse embryos. The capacity of this dish to maintain medium osmolarity with minimal mineral oil usage represents a breakthrough that may advance embryo culture techniques for various mammals, including human in vitro fertilization and embryo transfer programs.

Real-time counting of wheezing events from lung sounds using deep learning algorithms: Implications for disease prediction and early intervention.

This pioneering study aims to revolutionize self-symptom management and telemedicine-based remote monitoring through the development of a real-time wheeze counting algorithm. Leveraging a novel approach that includes the detailed labeling of one breathing cycle into three types: break, normal, and wheeze, this study not only identifies abnormal sounds within each breath but also captures comprehensive data on their location, duration, and relationships within entire respiratory cycles, including atypical patterns. This innovative strategy is based on a combination of a one-dimensional convolutional neural network (1D-CNN) and a long short-term memory (LSTM) network model, enabling real-time analysis of respiratory sounds. Notably, it stands out for its capacity to handle continuous data, distinguishing it from conventional lung sound classification algorithms. The study utilizes a substantial dataset consisting of 535 respiration cycles from diverse sources, including the Child Sim Lung Sound Simulator, the EMTprep Open-Source Database, Clinical Patient Records, and the ICBHI 2017 Challenge Database. Achieving a classification accuracy of 90%, the exceptional result metrics encompass the identification of each breath cycle and simultaneous detection of the abnormal sound, enabling the real-time wheeze counting of all respirations. This innovative wheeze counter holds the promise of revolutionizing research on predicting lung diseases based on long-term breathing patterns and offers applicability in clinical and non-clinical settings for on-the-go detection and remote intervention of exacerbated respiratory symptoms.

The effect of growth hormone on ovarian function recovery in a mouse model of ovarian insufficiency.

Objectives: To evaluate the effects and mechanisms of action of growth hormone (GH) in the recovery of ovarian function in ovarian insufficiency induced by cyclophosphamide (CP) in a mouse model. Materials and methods: After inducing ovarian insufficiency by administering 400 mg/kg of CP intraperitoneally to 6-week-old ICR mice, the mice were divided into four groups (control, CP, 1 mg/kg GH, and 2 mg/kg GH) with 10 mice in each group. GH was administered a week later for 7 days. Five mice from each group were sacrificed the next day, and their ovaries were collected for histological examination. The remaining mice were superovulated for in vitro fertilization (IVF). The terminal deoxynucleotidyl transferase dUTP-nick end labeling assay was performed to detect apoptosis. Masson's trichrome staining was used to analyze the degree of fibrosis. To quantify angiogenesis, CD31 immunohistochemistry was performed. Angiogenesis-related gene expression profiles were assessed using quantitative reverse transcription polymerase chain reaction. Results: CP induced the loss of non-growing (primordial and primary) follicles while GH significantly protected primordial follicles and increased follicular quality. The CP group showed a decrease in fertilization and blastocyst formation rates in IVF. In contrast, the GH treatment group showed dose-dependent enhanced IVF outcomes. Furthermore, GH treatment decreased apoptosis and stromal fibrosis and increased angiogenesis. Many genes involved in angiogenesis, especially Leptin (Lep), platelet endothelial cell adhesion molecule 1 (Pecam-1), and angiogenin (Ang) were up-regulated in the GH treatment groups. Conclusion: GH treatment may promote the recovery of ovarian function in ovarian insufficiency induced by the administration of CP via decreasing apoptosis and stromal fibrosis and upregulating Lep, Pecam-1, and Ang genes.

Ovastacin: An oolemma protein that cleaves the zona pellucida to prevent polyspermy.

Monospermy occurs in the process of normal fertilization where a single sperm fuses with the egg, resulting in the formation of a diploid zygote. During the process of fertilization, the sperm must penetrate the zona pellucida (ZP), the outer layer of the egg, to reach the egg's plasma membrane. Once a sperm binds to the ZP, it undergoes an acrosomal reaction, which involves the release of enzymes from the sperm's acrosome that help it to penetrate the ZP. Ovastacin is one of the enzymes that is involved in breaking down the ZP. Studies have shown that ovastacin is necessary for the breakdown of the ZP and for successful fertilization to occur. However, the activity of ovastacin is tightly regulated to ensure that only one sperm can fertilize the egg. One way in which ovastacin helps to prevent polyspermy (the fertilization of an egg by more than one sperm) is by rapidly degrading the ZP after a sperm has penetrated it. This makes it difficult for additional sperm to penetrate the ZP and fertilize the egg. Ovastacin is also thought to play a role in the block to polyspermy, a mechanism that prevents additional sperm from fusing with the egg's plasma membrane after fertilization has occurred. In summary, the role of ovastacin in monospermic fertilization is to help ensure that only one sperm can fertilize the egg, while preventing polyspermy and ensuring successful fertilization.

Epigenetic modulation of ferroptosis in cancer: Identifying epigenetic targets for novel anticancer therapy.

Ferroptosis is a newly recognized form of oxidative-regulated cell death resulting from iron-mediated lipid peroxidation accumulation. Radical-trapping antioxidant systems can eliminate these oxidized lipids and prevent disrupting the integrity of cell membranes. Epigenetic modifications can regulate ferroptosis by altering gene expression or cell phenotype without permanent sequence changes. These mechanisms include DNA methylation, histone modifications, RNA modifications, and noncoding RNAs. Epigenetic alterations in cancer can control the expression of ferroptosis regulators or related pathways, leading to changes in cell sensitivity to ferroptosis inducers or cancer progression. Epigenetic alterations in cancer are influenced by a wide range of cancer hallmarks, contributing to therapeutic resistance. Targeting epigenetic alterations is a promising approach to overcoming cancer resilience. However, the exact mechanisms involved in different types of cancer remain unresolved. Discovering more ferroptosis-associated epigenetic targets and interventions can help overcome current barriers in anticancer therapy. Many papers on epigenetic modifications of ferroptosis have been continuously published, making it essential to summarize the current state-of-the-art in the epigenetic regulation of ferroptosis in human cancer.

Targeting Nrf2 for ferroptosis-based therapy: Implications for overcoming ferroptosis evasion and therapy resistance in cancer.

Ferroptosis is a newly discovered form of programmed cell death caused by redox-active iron-mediated lipid peroxidation. Ferroptosis exhibits a unique morphological phenotype resulting from oxidative damage to membrane lipids. Ferroptosis induction has been shown to be effective in treating human cancers that rely on lipid peroxidation repair pathways. Nuclear factor erythroid 2-related factor 2 (Nrf2) can control the regulatory pathways of ferroptosis, which involve genes associated with glutathione biosynthesis, antioxidant responses, and lipid and iron metabolism. Resistant cancer cells often utilize Nrf2 stabilization by Keap1 inactivation or other somatic alterations in the genes from the Nrf2 pathway, which can confer resistance to ferroptosis induction and other therapies. However, pharmacological inactivation of the Nrf2 pathway can sensitize cancer cells to ferroptosis induction. Inducing lipid peroxidation and ferroptosis through regulating the Nrf2 pathway is a promising strategy for enhancing the anticancer effects of chemotherapy and radiation therapy in therapy-resistant human cancers. Despite promising preliminary studies, clinical trials in human cancer therapy have not yet been realized. A deeper understanding of their exact processes and efficacies in various cancers remains unsolved. Therefore, this article aims to summarize the regulatory mechanisms of ferroptosis, their modulation by Nrf2, and the potential of targeting Nrf2 for ferroptosis-based cancer therapy.

Unleashing Ferroptosis in Human Cancers: Targeting Ferroptosis Suppressor Protein 1 for Overcoming Therapy Resistance.

Ferroptosis, a recently identified form of regulated cell death characterized by the iron-dependent accumulation of lethal lipid peroxidation, has gained increasing attention in cancer therapy. Ferroptosis suppressor protein 1 (FSP1), an NAD(P)H-ubiquinone oxidoreductase that reduces ubiquinone to ubiquinol, has emerged as a critical player in the regulation of ferroptosis. FSP1 operates independently of the canonical system xc-/glutathione peroxidase 4 pathway, making it a promising target for inducing ferroptosis in cancer cells and overcoming ferroptosis resistance. This review provides a comprehensive overview of FSP1 and ferroptosis, emphasizing the importance of FSP1 modulation and its potential as a therapeutic target in cancer treatment. We also discuss recent progress in developing FSP1 inhibitors and their implications for cancer therapy. Despite the challenges associated with targeting FSP1, advances in this field may provide a strong foundation for developing innovative and effective treatments for cancer and other diseases.

Targeting Iron-Sulfur Clusters in Cancer: Opportunities and Challenges for Ferroptosis-Based Therapy.

Iron dysregulation is a hallmark of cancer, characterized by an overexpression of genes involved in iron metabolism and iron-sulfur cluster (ISC) biogenesis. Dysregulated iron homeostasis increases intracellular labile iron, which may lead to the formation of excess cytotoxic radicals and make it vulnerable to various types of regulated cell death, including ferroptosis. The inhibition of ISC synthesis triggers the iron starvation response, increasing lipid peroxidation and ferroptosis in cancer cells treated with oxidative stress-inducing agents. Various methods, such as redox operations, iron chelation, and iron replacement with redox-inert metals, can destabilize or limit ISC formation and function, providing potential therapeutic strategies for cancer treatment. Targeting ISCs to induce ferroptosis represents a promising approach in cancer therapy. This review summarizes the state-of-the-art overview of iron metabolism and ferroptosis in cancer cells, the role of ISC modulation in ferroptosis, and the potential of targeting ISCs for ferroptosis induction in cancer therapy. Further research is necessary to develop and validate these strategies in clinical trials for various cancers, which may ultimately lead to the development of novel and effective treatments for cancer patients.

The Interplay between Intracellular Iron Homeostasis and Neuroinflammation in Neurodegenerative Diseases.

Iron is essential for life. Many enzymes require iron for appropriate function. However, dysregulation of intracellular iron homeostasis produces excessive reactive oxygen species (ROS) via the Fenton reaction and causes devastating effects on cells, leading to ferroptosis, an iron-dependent cell death. In order to protect against harmful effects, the intracellular system regulates cellular iron levels through iron regulatory mechanisms, including hepcidin-ferroportin, divalent metal transporter 1 (DMT1)-transferrin, and ferritin-nuclear receptor coactivator 4 (NCOA4). During iron deficiency, DMT1-transferrin and ferritin-NCOA4 systems increase intracellular iron levels via endosomes and ferritinophagy, respectively. In contrast, repleting extracellular iron promotes cellular iron absorption through the hepcidin-ferroportin axis. These processes are regulated by the iron-regulatory protein (IRP)/iron-responsive element (IRE) system and nuclear factor erythroid 2-related factor 2 (Nrf2). Meanwhile, excessive ROS also promotes neuroinflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB forms inflammasomes, inhibits silent information regulator 2-related enzyme 1 (SIRT1), and induces pro-inflammatory cytokines (IL-6, TNF-α, and IL-1ß). Furthermore, 4-hydroxy-2,3-trans-nonenal (4-HNE), the end-product of ferroptosis, promotes the inflammatory response by producing amyloid-beta (Aß) fibrils and neurofibrillary tangles in Alzheimer's disease, and alpha-synuclein aggregation in Parkinson's disease. This interplay shows that intracellular iron homeostasis is vital to maintain inflammatory homeostasis. Here, we review the role of iron homeostasis in inflammation based on recent findings.

Promotion of ferroptosis in head and neck cancer with divalent metal transporter 1 inhibition or salinomycin.

Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells.

Targeting GPX4 in human cancer: Implications of ferroptosis induction for tackling cancer resilience.

Cancer metabolic alterations have been emphasized to protect cancer cells from cell death. The metabolic reprogramming toward a mesenchymal state makes cancer cells resistant to therapy but vulnerable to ferroptosis induction. Ferroptosis is a new form of regulated cell death based on the iron-dependent accumulation of excessive lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the core regulator of ferroptosis by detoxifying cellular lipid peroxidation using glutathione as a cofactor. GPX4 synthesis requires selenium incorporation into the selenoprotein through isopentenylation and selenocysteine tRNA maturation. GPX4 synthesis and expression can be regulated by multiple levels of its transcription, translation, posttranslational modifications, and epigenetic modifications. Targeting GPX4 in cancer may be a promising strategy for effectively inducing ferroptosis and killing therapy-resistant cancer. Several pharmacological therapeutics targeting GPX4 have been developed constantly to activate ferroptosis induction in cancer. The potential therapeutic index of GPX4 inhibitors remains to be tested with thorough examinations of their safety and adverse effects in vivo and clinical trials. Many papers have been published continuously in recent years, requiring state-of-the-art updates in targeting GPX4 in cancer. Herein, we summarize targeting the GPX4 pathway in human cancer, which leads to implications of ferroptosis induction for tackling cancer resilience.

Epithelial-mesenchymal plasticity: Implications for ferroptosis vulnerability and cancer therapy.

Cancers polarized to a mesenchymal or poorly differentiated state can often evade cell death induced by conventional therapies. The epithelial-mesenchymal transition is involved in lipid metabolism and increases polyunsaturated fatty acid levels in cancer cells, contributing to chemo- and radio-resistance. Altered metabolism in cancer enables invasion and metastasis but is prone to lipid peroxidation under oxidative stress. Cancers with mesenchymal rather than epithelial signatures are highly vulnerable to ferroptosis. Therapy-resistant persister cancer cells show a high mesenchymal cell state and dependence on the lipid peroxidase pathway, which can respond more sensitively to ferroptosis inducers. Cancer cells may survive under specific metabolic and oxidative stress conditions, and targeting this unique defense system can selectively kill only cancer cells. Therefore, this article summarizes the core regulatory mechanisms of ferroptosis in cancer, the relationship between ferroptosis and epithelial-mesenchymal plasticity, and the implications of epithelial-mesenchymal transition for ferroptosis-based cancer therapy.

Altered iron metabolism as a target for ferroptosis induction in head and neck cancer.

Iron is a mineral micronutrient essential for survival and vital functions in many biological processes in living organisms. Iron plays a crucial role as a cofactor of iron-sulfur clusters in energy metabolism and biosynthesis by binding with enzymes and transferring electrons to targets. Iron can also impair cellular functions by damaging organelles and nucleic acids by producing free radicals from redox cycling. Iron-catalyzed reaction products can induce active-site mutations in tumorigenesis and cancer progression. However, the boosted pro-oxidant iron form may contribute to cytotoxicity by increasing soluble radicals and highly reactive oxygen species via the Fenton reaction. An increased redox-active labile iron pool is required for tumor growth and metastasis, but the increased cytotoxic lipid radicals also lead to regulated cell death, such as ferroptosis. Therefore, this may be a major target for selectively killing cancer cells. This review intends to understand altered iron metabolism in cancers and discuss iron-related molecular regulators highly associated with iron-induced cytotoxic radical production and ferroptosis induction, focusing on head and neck cancer.

Lipid metabolism alterations and ferroptosis in cancer: Paving the way for solving cancer resistance.

Cancer often perturbs lipid metabolism, which leads to the alteration of metabolism intermediates, contributing to their deregulated growth and metastasis. Alteration of lipid metabolism shifting to contain more polyunsaturated fatty acids (PUFAs) in membrane phospholipids (PLs) also leads to cancer therapy resistance. High amounts of PL-PUFAs render cancer cells more vulnerable to lipid peroxidation (LPO), predisposing them towards ferroptosis, a new form of iron-dependent oxidative regulated cell death. The commitment of cancer undergoing ferroptotic cell death depends on the adaptive lipidome remodeling, LPO patterns, and LPO scavenging ability in heterogeneous cancer cells. Ferroptosis is receiving attention in cancer research as treating cancers, altering membrane lipid homeostasis, and refractory from conventional therapies. Therefore, a better understanding of the molecular underpinning of lipid metabolism alterations may provide new opportunities for solving cancer resistance. This review intends to understand altered lipid metabolism in cancers and discuss lipid composition and metabolic processes associated with ferroptosis induction in cancers.

Ferroptosis induction via targeting metabolic alterations in head and neck cancer.

Ferroptosis is a newly regulated cell death induced by the accumulation of iron-mediated lipid peroxidation. The alteration of cancer metabolism may contribute to proliferation, metastasis, and treatment resistance in human cancers, implicating the sensitivity to ferroptosis induction. Altered metabolism in cancer cells regulates oxidative stresses and changes metabolism intermediates, contributing to their deregulated growth and proliferation. Cancer metabolic changes toward the elevation of cellular free iron and polyunsaturated fatty acids sensitize cancer cells to lipid peroxidation toxicity tightly linked to ferroptosis. The altered metabolism in cancers can be served as a promising target to reverse cancer therapeutic resistance by ferroptosis induction to selectively kill cancer cells while sparing normal cells. The role of mitochondria and lipid metabolism in inducing ferroptosis in head and neck cancer (HNC) has been elucidated in previous studies. Ferroptosis is receiving attention in cancer research as treating cancers altering cellular metabolism and refractory from conventional therapies. More in-depth studies are needed to develop highly therapeutic drugs and practical methods to induce ferroptosis in diverse cancer cells and tumor microenvironments effectively. Therefore, this review intends to understand the altered metabolism and find new therapeutic possibilities using ferroptosis in HNC.

Thiol-yne click crosslink hyaluronic acid/chitosan hydrogel for three-dimensional in vitro follicle development.

There is a great deal of potential for in vitro follicle growth to provide an alternative approach to fertility preservation. This strategy reduces the possibility of cancer cells re-exposure after transplantation, and it does not require hormone stimulation. Adopting a three-dimensional (3D) culture method helps preserve the architecture of the follicle and promotes the maturity of oocytes. In order to maintain follicle morphology, enhance the quality of mature oocytes, and facilitate meiotic spindle assembly, the current work aimed to develop the 3D in vitro preantral mouse follicle culture method. Thiolated chitosan-co-thiolated hyaluronic (CSHS) hydrogel was designed to evaluate the effects of biomaterials on ovarian follicle development. Isolated follicles from mouse ovaries were randomly divided into alginate (Alg) as a 3D control, thiolated hyaluronic acid (HASH), and CSHS groups. Single follicle was encapsulated in each hydrogel, and performed for 10 days and subsequently ovulated to retrieve mature oocytes on day 11. CSHS hydrogel promoted follicle survival and oocyte viability with maintained spherical morphology of follicle. Matured oocytes with normal appearance of meiotic spindle and chromosome alignment were higher in the CSHS group compared with those in the Alg and HASH groups. Furthermore, CSHS increased expression level of folliculogenesis genes (TGFß-1, GDF-9) and endocrine-related genes (LHCGR, and FSHR). With various experimental setups and clinical applications, this platform could be applied as an alternative method to in vitro follicle culture with different experimental designs and clinical applications in the long-term period.

SLC7A11 as a Gateway of Metabolic Perturbation and Ferroptosis Vulnerability in Cancer.

SLC7A11 is a cell transmembrane protein composing the light chain of system xc-, transporting extracellular cystine into cells for cysteine production and GSH biosynthesis. SLC7A11 is a critical gateway for redox homeostasis by maintaining the cellular levels of GSH that counter cellular oxidative stress and suppress ferroptosis. SLC7A11 is overexpressed in various human cancers and regulates tumor development, proliferation, metastasis, microenvironment, and treatment resistance. Upregulation of SLC7A11 in cancers is needed to adapt to high oxidative stress microenvironments and maintain cellular redox homeostasis. High basal ROS levels and SLC7A11 dependences in cancer cells render them vulnerable to further oxidative stress. Therefore, cyst(e)ine depletion may be an effective new strategy for cancer treatment. However, the effectiveness of the SLC7A11 inhibitors or cyst(e)inase has been established in many preclinical studies but has not reached the stage of clinical trials for cancer patients. A better understanding of cysteine and SLC7A11 functions regulating and interacting with redox-active proteins and their substrates could be a promising strategy for cancer treatment. Therefore, this review intends to understand the role of cysteine in antioxidant and redox signaling, the regulators of cysteine bioavailability in cancer, the role of SLC7A11 linking cysteine redox signaling in cancer metabolism and targeting SLC7A11 for novel cancer therapeutics.